Incidence and Frequency of Pediatric Renal Transplantation

In 2016 about 19,000 kidney transplants were performed in the United States, and about 700 of these were in children younger than 18 years. In most years, pediatric patients comprise <5% of all transplant recipients. Although the number of pediatric transplants performed each year has generally varied by no more than 10%, the donor origin has undergone substantial changes. Living kidney donation is generally more prominent in children due to parental motivation to donate. With policies that increased availability to deceased donors for children, living donations fell. In 2016 living donation accounted for 39% of all kidney transplants in the United States, but for 65% of kidney transplants to children. Most of these are living-related, but similar to the adult population, increasing percentages of living-unrelated or paired-exchange donors are being reported.

In the 1980s there was a tendency to preferentially place kidneys recovered from infants into infant recipients (size matching), with high thrombosis rates and disastrous consequences for patient and graft survival. As a result of widespread dissemination of these data, there has been a marked change in practice. The majority of DD kidneys for children are now recovered from adult donors. This change in allocation of kidneys from young donors led to improvement in graft survival. Many programs reserve grafts from very young donors for en bloc transplantation into older recipients.

Etiology of End-Stage Renal Disease in Children

ESRD in children is generally due to congenital or inherited diseases. In reviewing 11,603 transplants in the NAPRTCS database, the most common congenital diagnoses found are aplastic/hypoplastic/dysplastic kidneys and obstructive uropathy, with each representing about 15% of the patients ( Table 43.1 ). Among glomerular disorders, focal segmental glomerulosclerosis (FSGS) is the most common at 11%. The primary diagnosis also varies with the race of the recipient. Caucasian children account for 59% of all recipients; however, Caucasian children account for less than 50% of the children transplanted for FSGS. Table 43.1 shows the primary diagnoses by gender and race of 10,632 children who received a transplant as recorded by NAPRTCS since 1987 and the percentage of biopsy-proven diagnoses. It is important to observe that the biopsy confirmation of the primary diagnosis was made in 94% of FSGS, in 87% of systemic immunological diseases, and in 90% of congenital nephrotic syndrome patients. The information regarding primary diagnosis is critical in predicting graft survival and recurrence of the original disease, as discussed later.

Indications for Renal Transplantation in Children

There has been a substantial change in long-term renal allograft outcome for children across the world during the past three decades. Previously, young children were thought to have poor short- and long-term graft survival related to several factors, most prominently a proposed heightened immune response, especially in infants. The most recent comprehensive registry reviews have clearly demonstrated a dramatic reversal in outcomes with marked improvements in patient and kidney graft survival for infants and young children. Indeed, several analyses have identified these very young recipients as now having the best long-term survivals of all age groups. Thus children of all ages are excellent transplant candidates. Therefore by the time that the child has reached chronic kidney disease (CKD) stage 4 to 5, planning for kidney transplantation and pretransplant preparation should have begun. There are very few contraindications to kidney transplantation in children. Perhaps the only two are the presence of another otherwise-fatal condition with a short projected survival, such as metastatic Wilms’ tumor and severe neurological compromise. About 75% of children are treated with a course of chronic dialysis before renal transplantation, but unless there is a need for specific pretransplant preparation, there is no advantage to pretransplant dialysis. For adults, preemptive renal transplantation has a survival advantage, whereas in children, although advantage is harder to show, there is no detriment.

Recipient Age at Transplantation

Kidney transplantation before 6 months of age or in a recipient who weighs less than 6 kg is very unusual. Since 1987, NAPRTCS has recorded approximately 560 transplants performed in children younger than 12 months, around 5.3% of the total. The yearly number has dropped in more recent years. Because infants and adolescents have different risk factors for both patient and graft survival, children frequently have been grouped into five age categories: 0 to 1 year, 2 to 5 years, 6 to 12 years, 13 to 17 years, and 18 to 21 years of age. In 1987 25% of all pediatric transplants were performed in children 0 to 5 years of age, whereas by 2010 the same age group accounted for 20%. The decreased number of transplants in this group is likely due to greater surgical challenges in these small recipients, combined with the development of better dialysis for infants. However, excellent results have been obtained in very young patients in some individual centers. The concept of a heightened immune response in young recipients is controversial. Thus the unique problems associated with transplantation in young recipients may be related to infections, technical issues, and differences in pharmacokinetics rather than to their immune response.

There has been a substantial change in long-term renal allograft outcome for children during the past three decades. Infants have flipped from poor long-term allograft survival to the best long-term survival. Conversely, however, adolescents were subsequently noted to have a higher rate of late acute rejections ; infants may have a lower rate of acute rejection than older children. An important analysis of the United Network for Organ Sharing (UNOS) data demonstrated that in the mid-1990s, short-term pediatric renal transplant survival rates became comparable to those in adults. The most recent comprehensive registry reviews have clearly demonstrated a dramatic reversal in outcomes. Improvements in surgical technique, donor selection, immunosuppression practices, the enhanced experience of specialized pediatric transplant teams, and the development of multicenter research consortia have all led to marked improvements in patient and kidney graft survival for infants and young children.

Currently, pediatric recipients have 5-year allograft survival rates of 86.5% if from an LD and 83.2% if from a DD, which is comparable to rates seen in adults. Unfortunately, this excellent outcome is not seen in adolescents, whose 5-year graft survivals are less than 80% and whose 10-year graft survival is only 50%, worse than all other age groups except the most elderly. The graft failure risk dramatically increases between the ages of 11 and 24.

Recipient Preparation

Before a child can undergo renal transplantation, the problems caused by CKD must be addressed and optimized if possible. In those cases where ESRD is due to urological abnormalities, corrective reconstructive surgery should be undertaken, especially to the lower urinary tract, before transplantation. Two of the major consequences of CKD are anemia and growth retardation, both of which should be addressed before transplantation. A recent report of final adult height in pediatric renal transplant recipients suggests that the current improvement in final adult height posttransplantation is more related to improving height deficits before transplantation than to any net gains achieved after transplantation. Uremia also leads to wasting and malnutrition in the child, and this can compromise the success of the procedure. For example, prophylactic native nephrectomy and reversal of protein wasting and malnutrition improve the outcome of transplantation in children with congenital nephrotic syndrome. Careful preparation is particularly important in children undergoing preemptive transplants. Because live viral vaccines are generally not indicated in chronically immunosuppressed patients, children should receive all appropriate vaccines pretransplantation. Whereas guidelines exist for the evaluation of the adult transplant recipient, there are no similar published reports for pediatric patients.

Donor Preparation

Technical Issues in Transplantation

The operative technique differs based on the weight of the child. For children less than 15 kg, the transplant is performed through a midline incision, and the large abdominal vessels are used. After reflection of the right colon, the aorta and the inferior vena cava are exposed. The aorta is mobilized from above the inferior mesenteric artery to the external iliac artery on the right side. After the lumbar branches are ligated and divided, the iliac arteries and the inferior mesenteric are encircled. Next the inferior vena cava is mobilized from the left renal vein to the iliac veins. After the lumbar veins are ligated, the iliac veins are encircled. The donor renal vein is anastomosed to the recipient vena cava in an end-to-side technique. The donor renal artery is then anastomosed to the recipient aorta in an end-to-side fashion. Careful attention must be paid to the recipient’s hemodynamic response upon clamping and unclamping of the major vessels, and it is desirable to maintain a central venous pressure of 15 to 18 cm H ₂ O before unclamping. The perfusion of the transplanted kidney may be slow because a large adult kidney will take up a significant portion of the normal pediatric blood volume. Hemodynamic studies suggest that the cardiac output of infants must double to perfuse the adult donor kidney adequately. Thus volume replacement is critical when the kidney is large relative to the infant’s body ( Fig. 43.1 ). The ureteral anastomosis is performed by implanting the donor’s ureter into the recipient’s bladder, most commonly these days via a nonrefluxing extravesical (Lich-Grégoire) approach rather than an intravesical approach (Politano-Leadbetter procedure) because it is faster, a separate cystotomy is not required, and less ureteral length is necessary, thus assuring a distal ureteral blood supply.

^99m Tc-MAG3 radionuclide renal scan in a 9-month-old infant who received a living donor renal transplant from his father. The graft is intraperitoneal and occupies most of the right side of the peritoneal space. Note the relative sizes of the graft and the heart.

From Smith JM, Martz K, Blydt-Hansen TD: Pediatric kidney transplant practice patterns and outcome benchmarks, 1987-2010: a report of the North American Pediatric Renal Trials and Collaborative Studies. Pediatr Transplant . 2013;17(2):149-157.

The transplantation technique used in children with a body weight greater than 15 kg is similar to that employed in adults. Unlike the transperitoneal approach necessary in younger children, this transplant is extraperitoneal, with the renal vein anastomosed to the common iliac or the external iliac vein. The arterial anastomosis can be to either the common iliac or internal iliac artery. The ureterovesicular anastomosis is performed using the techniques described earlier.

Evaluation of Graft Dysfunction

At the completion of the vascular anastomosis and release of the vascular clamps, immediate function of the transplanted kidney is demonstrated by the production of urine. Various causes, however, may prevent initial function, and evaluation of immediate nonfunction and the differential diagnosis of this condition are critical components of the transplant physician’s role (see Chapter 36 ).

Delayed Graft Function

A well-functioning kidney graft should lead to normal renal function within 2 to 3 days. The lack of attainment of normal renal function, as would be demonstrated by a fall of the serum creatinine to normal levels, is termed delayed graft function (DGF). There is no consensus concerning the definition of DGF. In some settings, DGF is used only to distinguish recipients who require dialysis after transplantation, but that is a very stringent definition. Acute tubular necrosis (ATN) represents the most frequent cause of immediate graft nonfunction in children. Current data from the NAPRTCS show that ATN was observed in 4.8% of LD and in 14.7% of DD index transplants (Karen Martz, personal communication). Because the NAPRTCS definition for ATN is the stringent “requiring the use of dialysis in the first posttransplant week,” these figures probably underrepresent the actual incidence of ATN. The risk for early ATN is related to factors such as prior transplants, prolonged cold ischemia, absence of prophylactic antibody therapy, and the use of more than five pretransplant blood transfusions. The diagnosis is confirmed in most cases by Doppler sonography or the use of radionuclide scan ( Fig. 43.2 ). If recovery of graft function is delayed, however, a transplant biopsy may be necessary, because other diagnostic tests cannot distinguish between ATN and rejection or recurrence of primary disease. Importantly, early acute rejection can mimic ATN or coexist with it. The presence of ATN does not auger well for the transplant, because the acute rejection rate jumps from ∼20% to 30% in LD and 40% in DD transplants to children. Long term, there is a 15% to 20% drop in graft survival in children if ATN occurs immediately posttransplant.

^99m Tc-MAG3 radionuclide renal scan of a deceased donor renal transplant in a 15-year-old boy performed on the first postoperative day. The cold ischemia time exceeded 24 hours, and the recipient experienced oliguric acute tubular necrosis. Note the good perfusion, followed by little excretion and “washout” of the tracer from the graft.

Importantly, although the incidence of DGF is increased when a donation after cardiac death (DCD) donor is used, the detrimental effect of DGF on long-term outcomes in this setting does not appear to be as severe as when it occurs after living donation or after transplantation from brain-dead DDs.

Graft Thrombosis

Graft thrombosis is an almost unique complication of Pediatric Transplantation. Although usually a major cause of immediate graft nonfunction, it can be seen later on in the course and has been recorded to occur as late as 15 days posttransplantation after initial engraftment and function. Graft thrombosis has been the third most common cause of graft failure in pediatric renal transplantation and may rise to second as acute rejection rates continue to fall. The critical nature of this complication can be appreciated from the fact that it accounts for ∼10% of graft failure in index transplantation and 12% in repeat transplants in the NAPRTCS registry. A dreaded event, this condition is irreversible in most cases and necessitates removal of the graft. Graft thrombosis should be suspected in cases where there has been immediate function followed by the development of oligoanuria. The diagnosis is established by sonography or radionuclide scan using diethylenetriamine pentaacetic acid (DTPA) or MAG3, which reveals a photopenic defect with no uptake by the transplant kidney ( Fig. 43.3 ).

^99m Tc-MAG3 radionuclide renal scan in a 6-year-old girl with focal segmental glomerulosclerosis who received a living donor renal transplant, performed 16 hours postoperation. Note the photopenic area in the right abdomen, indicating thrombosis of the graft with no perfusion.

Because the outcome of graft thrombosis is uniformly dismal, numerous studies have been conducted in an attempt to understand and anticipate this complication. The etiology of graft thrombosis is multifactorial, but it is more commonly seen in young recipients. In a special study of 2060 LD and 2334 DD kidneys, the NAPRTCS has shown that a history of prior transplantation increases the risk, whereas increasing recipient age has a protective effect for LD kidneys. The prophylactic use of antilymphocyte antibody also decreases the risk, and this may be particularly true for the monoclonal interleukin-2 receptor (IL-2r) antibodies. For DD kidneys, a cold ischemia time longer than 24 hours increases the risk for thrombosis. The use of antibody induction therapy, the use of donors older than 5 years of age, and increasing recipient age were factors that decreased the risk for thrombosis. One study showed that centers that performed fewer infant transplants had higher rates of graft thrombosis, and other studies suggested that pretransplant use of peritoneal dialysis increased the risk for thrombosis. Some centers routinely administer anticoagulants to pediatric recipients at high risk for graft thrombosis, but no clinical studies of their effectiveness have been performed, and their use is not without complications.

Obstruction, Urinary Leak, and Urological Complications

An uncommon but correctable cause of immediate graft dysfunction is obstruction of the urinary flow, which presents as decreasing urine output and the development of hydronephrosis. An ultrasound or radionuclide scan with a furosemide washout enables the clinician to establish this diagnosis. Obstruction can be due to kinking of the ureter, to edema or blockage of the implantation site of the ureter, or to development of a lymphocele. A more ominous cause of immediate nonfunction is the rare case of urinary leak due to disintegration of the distal ureter or rupture of the bladder. This condition is extremely painful due to the extravasation of urine into the pelvis or peritoneal cavity and is established by radionuclide scan ( Fig. 43.4 ). The appearance of the tracer in the peritoneal cavity or in the scrotal, vulvar, or inguinal area clinches the diagnosis, and immediate surgical correction is necessary.

^99m Tc-MAG3 radionuclide renal scan in an 8-year-old girl who received a deceased donor renal transplant, performed 12 hours postoperation. Note the good perfusion of the graft and the rapid concentration and excretion from the kidney. Tracer, however, rapidly accumulates in the right lower quadrant, outside of the bladder. Investigation demonstrated a traumatic bladder rupture.

Immunosuppression Strategies

Between 80% and 90% of pediatric kidney transplant recipients currently receive antibody-based induction therapy after kidney transplantation, with the majority of those receiving T-cell depleting agents. In addition, most children receive triple maintenance immunosuppression with tacrolimus, mycophenolate mofetil (MMF), and steroids. As shown in the NAPRTCS annual report, the “typical” immunosuppression protocols have changed frequently over the past two decades ( Fig. 43.5 ). However, it also appears as though children who begin treatment under one combination stay on that regimen. Several recent multicenter research efforts have been directed toward an attempt to decrease the number of types of chronic immunosuppression, with corticosteroids and calcineurin inhibitors (CNIs) being the most common medications targeted for removal. Several multicenter trials have reported success in avoiding or withdrawing corticosteroids, although some of these have had substantial adverse effects. There have also been reports of avoidance of CNI in children, a move designed to prevent nephrotoxicity. At least one of these trials resulted in excellent long-term graft function but had a high rate of early acute rejections. In general, children metabolize immunosuppressive drugs faster than adults. Thus data show that young children often need cyclosporine dosing three times a day or sirolimus twice a day, versus the standard dosing used in adults. Body surface area dosing of drugs may be more accurate than per-kilogram dosing in young children.

Maintenance immunosuppression in pediatric living donor renal transplant recipients by transplant year.

From Smith JM, Martz K, Blydt-Hansen TD. Pediatric kidney transplant practice patterns and outcome benchmarks, 1987-2010: a report of the North American Pediatric Renal Trials and Collaborative Studies. Pediatr Transplant. 2013;17(2):149-157.

Hyperacute Rejection

Hyperacute rejection is the result of specific recurrent antidonor antibodies against human leukocyte antigen (HLA), ABO, or other antigens. Irreversible rapid destruction of the graft occurs. Histologically there is glomerular thrombosis, fibrinoid necrosis, and polymorphonuclear leukocyte infiltration. In the early years of transplantation, when the HLA-matching techniques were not well developed, hyperacute rejection was more common. As in adults, hyperacute rejection has become exceedingly rare in children. The only treatment is surgical removal of the allograft. Graft failure from hyperacute rejection is reported in only 0.7% of all index or subsequent transplants in the last NAPRTCS report.

Acute Rejection

Information regarding the incidence and outcome of acute rejection in pediatric renal transplantation is available from the NAPRTCS data. Because NAPRTCS receives data from multiple centers that use different diagnostic and treatment protocols, the definition of a rejection episode is based upon the circumstance of a patient having been treated with antirejection therapy, although biopsy confirmation is becoming more common. A remarkable decrease in the incidence of acute rejection has occurred over the past 30 years ( Table 43.2 ). In a study of two cohorts of pediatric renal transplant recipients (1469 in 1987–89; 1189 in 1997–99), the rejection ratios dropped from 1.6 to 0.7 per patient. Sixty percent of the latter group were rejection-free compared with 29% of the former, and 1-year graft survival was 94% compared with 80%. Historically, more than half of the patients experienced a rejection in the first posttransplant weeks; now the great majority of patients experience a rejection-free first year. In the most recent cohorts, the 1-year acute rejection rates are 8.6% for LD transplants and 16.6% for DD transplants.

Risk factors for rejection after DD transplantation include the absence of prophylactic depleting antibody induction therapy, donor age younger than 5 years, African American race, and no antigen D–related (DR) matches. Risk factors for rejection after LD transplantation are the absence of lymphocyte-depleting antibody induction and one or two DR mismatches, African American race, and ATN. In an earlier study, the NAPRTCS noted that when reviewed by age groupings, rejection ratios, time to first rejection, and the mean number of rejection episodes were not different; however, for the initial rejection episode, recipients younger than 6 years of age had significantly increased irreversible rejections leading to graft loss. On the other hand, data from surveillance transplant biopsies suggest equivalent rejection responses in all groups. Most recent Scientific Registry of Transplant Recipients (SRTR) data demonstrated that infants and young children now have the best outcomes of all age groups. Thus either the proposed heightened immune response has been overcome by improved immunosuppression or the cause of previously poor outcome was related to other factors.

Chronic Allograft Dysfunction

The gradation from acute to chronic rejection is gradual; however, many biopsies may show features of both, and some characteristic vascular changes of chronic rejection may be seen early. The clinical picture is that of gradually declining renal function together with varying degrees of proteinuria and hypertension. The clinical condition may be referred to as transplant glomerulopathy, chronic rejection, chronic allograft dysfunction (CAD), chronic allograft nephropathy (CAN), or interstitial fibrosis and tubular atrophy (IFTA). The succession of names reflects lack of clarity of the etiology, clinical course, or treatment of this disorder. Nonetheless, this process, which will be referred to as CAD in this chapter, is the leading cause of graft loss after kidney transplantation in children.

An ongoing controversy exists as to whether the changes seen in chronic rejection are immune mediated, secondary responses to infection, ischemic in nature, or nonimmunological injury due to hyperfiltration. Data in children have shown clearly that acute rejection is a predictor of chronic rejection. In a study of 1699 LD and 1795 DD recipients, NAPRTCS noted that acute rejection was a relative risk (RR) factor for chronic rejection (RR = 3.1) and that multiple acute rejections increased the RR to 4.3. Late acute rejections are also clinical correlates of chronic rejection. Even if acute rejection is the most critical element in the genesis of chronic rejection, other immune mechanisms may mediate its progression, such as antibodies directed against the donor, major histocompatibility complex class I–related chain A (MICA), endothelial cells, and B lymphoblasts. Gene expression profiles in graft biopsies of patients with established CAD demonstrate upregulation of profibrotic and growth factors, and now such profiles may be able to predict later CAD.

Symptomatic therapy is currently the only available method of dealing with CAD. Hypertension should be controlled, and the proteinuria may occasionally respond to angiotensin-converting enzyme (ACE) inhibitors; however, renal function will generally continue to decline. In children, CAD produces an additional burden because decreased renal function will result in deceleration of growth. It is in this context that prevention of chronic rejection by early aggressive therapy in patients who have had an episode of acute rejection may be rewarding. Because currently available immunosuppressive medications have been unsuccessful in preventing or slowing the progression of chronic rejection , the use of regimens without steroids or immunosuppressives other than those currently approved may be reasonable, such as the use of costimulation blockade rather than nephrotoxic CNIs. Although some programs have concluded that these techniques might be beneficial after CAN is established, there may be a point at which substitution of nonnephrotoxic agents is not helpful. The presence of heavy proteinuria in recipients with CAD may also predict lack of benefit of changing chronic immunosuppression.

Recurrent Kidney Disease

Some diseases will recur in a transplanted kidney, and the recurrent disease may lead to loss of the graft, as it had done to the native kidneys previously. Recurrence of the original disease is the cause of 7% of all graft losses, and it is the cause of up to 9.5% of graft losses in subsequent transplants. Thus recurrence is one of the top four causes of all graft losses to children, which is unlike graft losses to adults. The 5-year LD graft survival for children with FSGS is 71%, and for children with glomerulonephritis it is 77%, in contrast to all other causes of ESRD, in which 5-year graft survival is greater than 83%. Several other pediatric diseases also recur posttransplant. In particular, atypical hemolytic uremic syndrome (HUS) from genetic deficiencies of complement inhibitors can recur in 20% to 80% and is the attributable cause of graft loss in 10% to 80%, especially for factor H mutations. Membranoproliferative glomerulonephritis (MPGN) type II, also related to complement cascade, has very high recurrence rates of 66% to 100% and attributable graft loss rates of 25% to 60%. Hyperoxaluria or oxalosis, a genetic disease, recurs in 80% to 100% and is the attributable cause for graft loss in 90% to 100%. More details are described later.